The present study investigated the mnemonic consequences of muscarinic blockade in rats pretreated with the serotonergic depleter p-chloroamphetamine (PCA). Subjects were initially injected with either PCB (2.5 mg/kg) or saline (SAL) approximately 1 week prior to testing on a working memory version of the Morris water maze (four daily trials for 4 days). Fifteen minutes before each daily session, PCA- and SAL-pretreated subjects were injected either with SAL or with one of two doses of scopolamine (SCOP; 0.5, 1.0 mg/kg). Latency to find the platform on each trial served as the major dependent measure. The results indicated that SCOP increased escape latencies. However, the dose needed to produce this effect was dependent upon whether subjects were pretreated with PCA. Significant increases in escape latencies in SAL-pretreated rats were induced with 1.0 mg/kg SCOP (on Day 1), while 0.5 mg/kg SCOP produced the same effect in PCB-pretreated subjects (on Days 1-4). Thus, although it was clearly demonstrated that muscarinic blockade did impair spatial working memory, the present data indicated that the dose necessary to produce this effect was dependent upon the status of the serotonergic system. More generally, these results imply that the cholinergic and serotonergic systems interact in a functionally important, as yet undetermined manner.